Combined toxicity of prenatal bacterial endotoxin exposure and postnatal 6-hydroxydopamine in the adult rat midbrain

• Published in: Neuroscience Vol. 124; no. 3; pp. 619 - 628
• Main Authors: Ling, Z.D, Chang, Q, Lipton, J.W, Tong, C.W, Landers, T.M, Carvey, P.M
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 2004; Elsevier
• Subjects: 6-hydroxydopamine; Animals; Animals, Newborn; Biological and medical sciences; Cell Death - drug effects; Cell Death - physiology; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disease Models, Animal; dopamine; Dopamine - metabolism; Encephalitis - chemically induced; Encephalitis - pathology; Encephalitis - physiopathology; Endotoxins - toxicity; Female; Fundamental and applied biological sciences. Psychology; IL-1β; Interleukin-1 - metabolism; lipopolysaccharide; Lipopolysaccharides - toxicity; Male; Medical sciences; Nerve Degeneration - chemically induced; Nerve Degeneration - pathology; Nerve Degeneration - physiopathology; Neurology; Neurons - drug effects; Neurons - microbiology; Neurons - pathology; Oxidopamine - toxicity; Parkinson Disease - etiology; Parkinson Disease - pathology; Parkinson Disease - physiopathology; Parkinson's disease; Pregnancy; prenatal; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Substantia Nigra - drug effects; Substantia Nigra - physiopathology; TNFα; Tumor Necrosis Factor-alpha - metabolism; Vertebrates: nervous system and sense organs; TNFα; VTA; Parkinson's disease; E; ir; IL-1β; EDTA; LPS; EU; P; 6OHDA; HVA; BV; PD; TH; prenatal; HBSS; SN; lipopolysaccharide; dopamine; DA; HPLC; ELISA; Rat; Toxicity; Central nervous system; Parkinson disease; Oxidopamine; Prenatal; Lipopolysaccharide; Degenerative disease; Tumor necrosis factor α; Nervous system diseases; Dopamine; Cytokine; Rodentia; Interleukin 1β; Midbrain; Catecholamine; Cerebral disorder; Vertebrata; Mammalia; Animal; Central nervous system disease; Neurotransmitter; Extrapyramidal syndrome
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2003.12.017

We previously reported that injection of the Gram (−) bacteriotoxin, lipopolysaccharide (LPS), into gravid females at embryonic day 10.5 led to the birth of animals with fewer than normal dopamine (DA) neurons when assessed at postnatal days (P) 10 and 21. To determine if these changes continued into adulthood, we have now assessed animals at P120. As part of the previous studies, we also observed that the pro-inflammatory cytokine tumor necrosis factor α (TNFα) was elevated in the striatum, suggesting that these animals would be more susceptible to subsequent DA neurotoxin exposure. In order to test this hypothesis, we injected (at P99) 6-hydroxydopamine (6OHDA) or saline into animals exposed to LPS or saline prenatally. The results showed that animals exposed to prenatal LPS or postnatal 6OHDA alone had 33% and 46%, respectively, fewer DA neurons than controls, while the two toxins combined produced a less than additive 62% loss. Alterations in striatal DA were similar to, and significantly correlated with (r 2=0.833) the DA cell losses. Prenatal LPS produced a 31% increase in striatal TNFα, and combined exposure with 6OHDA led to an 82% increase. We conclude that prenatal exposure to LPS produces a long-lived THir cell loss that is accompanied by an inflammatory state that leads to further DA neuron loss following subsequent neurotoxin exposure. The results suggest that individuals exposed to LPS prenatally, as might occur had their mother had bacterial vaginosis, would be at increased risk for Parkinson's disease.